A Practical Approach, Second Edition=Ronald D. Ho.pdf

PRINCIPLES OF DEVELOPMENTAL TOXICOLOGY REVISITED 7this to be true for a strain of mice heterozygous at the AHH (aryl hydrocarbon hydroxylase) locus,where some fetuses lack the induction receptor. 24 This receptor responds to aryl hydrocarbons, suchas TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), forming a complex involved in activating the genesfor cytochrome P-450 monooxygenases, a process thought to be involved in initiating the toxiceffects of TCDD.2. Susceptibility to Teratogenesis Varies with the Developmental Stageat the Time of Exposure to an Adverse Influence 15Development can be roughly divided into three periods with regard to susceptibility to toxic insult:a. PredifferentiationIf damaged during this period, the embryo typically either dies or completely repairs the damage,an “all or none” effect. There are some exceptions, however, such as the effects of x-rays or certainhighly potent genotoxic chemicals, and their effects may be genetically mediated. 25b. Early Differentiation or Early OrganogenesisThis occurs roughly from days 9 through 15 in the rat and days 9 through 18 in the rabbit (day onwhich mating was confirmed is day 0), with the timing varying by species (see Chapter 6, Table1 for others). Organ primordia, foundations for later development, are laid down at this time. Theembryo is most susceptible to induction of malformations during this period of development becauseonce the basic structures are formed, it becomes increasingly difficult to alter them structurally.Organs whose development is multiphasic, such as the eye and the brain, tend to have more thanone susceptible period.c. Advanced — or Late — OrganogenesisThis period is largely occupied with histogenesis and functional maturation. Insults during thisperiod mainly cause growth retardation, developmental delay, or functional disturbances, particularlyneurobehavioral problems, as the brain matures relatively late. However, even at this time,interrupted blood supply to a localized area or structure (e.g., because of an amniotic band) cancause degeneration of that area or structure, resulting in a malformation.A malformation may sometimes occur well after the initiating toxic insult, and this might bedue to alteration of biochemical events, such as gene activation and mRNA synthesis, that mayoccur prior to organ differentiation. This might also be due to alteration of an earlier event in asequence of events leading up to the formation of an organ — for example, interference with aninduction early in a “chain of inductions.”Organisms tend to be significantly more sensitive to many adverse environmental influencesduring early developmental stages, although this differential may not be quite as universallyapplicable in mammals as was once thought. And even though the human gestation period is long,the portion of that time spent in early organogenesis is fortunately relatively short; thus, the humanembryo is not at peak risk in comparison with its total gestation length. Increased sensitivity,especially during early organogenesis, apparently occurs because many complex and alterableevents are taking place. Many tissues are undergoing rapid cell division, and the embryo, and to aconsiderable extent, the fetus, has much less capacity to metabolize xenobiotics than does the adult.Some embryos, such as those of rodents, however, can be induced to biotransform a significantamount of certain developmental toxicants. Thus, metabolism can, in some cases, actually activatea toxicant, increasing its effects on the conceptus.© 2006 by Taylor & Francis Group, LLC